The rate of granulocyte production is so commonly increased during the course of immunologic reactions to disease that it has long been considered likely that specific cells within the immune system must be capable of directly stimulating granulopoiesis. Within recent months it has become clear that monocytes and T lymphocytes - two important classes of immunologically active cells - synthesize and secrete growth factors which stimulate both the proliferation and differentiation of myeloid progenitor cells. Very recently, three of these granulocyte and macrophage colony- stimulating factors have been purified, cloned, and expressed as recombinant proteins. The purpose of this research is to investigate the subcellular mechanisms by which these protein regulators exert their effects on cells of the granulocyte and monocyte lineage. We plan to study in detail their effects on transduction pathways and intracellular "signals" known to couple membrane-active ligands to a diverse array of subcellular responses. These studies will include measurement of their effects on intracellular calcium and other cations, on protein kinases, phospholipases, and other enzymes active in intracellular signalling, and on the functional activation of microbicidal and cytotoxic functions in phagocytes. Through these studies, we hope to gain insight into the mode of actions of these potentially important regulators of human granulopoiesis.